Project Summary/Abstract Currently, clinical applications of intravascular catheters suffer from major challenges: 1) platelet activation and surface-induced thrombosis, 2) biofouling of surfaces with proteins and bacteria, and 3) infection. Thrombus formation can further lead to obstruction of blood vessels, catheter malfunction, or even life-threatening situations such as embolism. Bacterial contamination of catheters causes more than 28,000 deaths per year in the United States, as well as costing the healthcare industry a staggering $2.3 billion. Commercial catheters with heparin- bonded surfaces are available to prevent clotting, but do little to prevent infections. In additions, catheters coated with antiseptics or antibiotics decrease the risk of bacterial infection, but do not prevent biofilm formation that shields bacteria from antibiotics. Therefore, there is a necessity and opportunity to combine strategies for preventing thrombosis and infection into single implantable device coatings for enhanced patency and safety. Our work and others have demonstrated that nitric oxide (NO) release from polymer surfaces can prevent platelet activation and bacterial infection. This technology mimics the vascular endothelial cells lining the blood vessels, as well as other cells in our bodies, producing NO locally to prevent clotting and bacterial biofilm and subsequent infections. Recently we discovered that all of the positive effects can be achieved from polymers doped with the NO donor molecule S-nitroso-N-acetylpenicillamine (SNAP), which is nontoxic, inexpensive, and easy to synthesize. Nitric oxide release alone can inhibit platelet function locally at the polymer/blood interface, but it does not prevent fibrinogen adsorption and fibrin formation which plays a key role in a clot formation. Liquid- infused surfaces exhibit resistance to biofouling and protein adsorption. Our recent work has shown that combining slippery tethered liquid-perfluorocarbon (TLP) surfaces with polymers impregnated with NO-releasing moieties reduces protein adsorption and platelet adhesion/activation significantly better than NO-releasing polymers alone. The goal of this proposal is to develop, optimize, and evaluate a novel polymer that will combine agents that inhibit platelet adhesion and activation via impregnated NO-releasing molecules as well as inhibit biofouling using the liquid-infused TLP surfaces. The biomaterials laboratory directed by Dr. Brisbois will develop the synthesis and polymer fabrication methods, optimize the NO release levels, evaluate the durability properties, study the sterilization/storage stability, and evaluate the antimicrobial properties against common microbes associated with catheter infections. Dr. Handa?s laboratory will study the blood-material interactions and also conduct the chronic animal studies to evaluate the catheters for thrombosis and infection. The new polymers will be applicable to any blood-contacting device; however, this proposal will focus on studying the combined antifouling and NO-releasing effects in long-term (up to 30 d) intravascular catheters on clotting and infection. Successful completion of this project will allow progression to early clinical trials and development of a new generation of catheters that can reduce complications while improving the success of patient care.